Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations

Abstract

We sequenced 61 patients with various idiopathic generalized epilepsy (IGE) syndromes for mutations in the EFHC1 gene. We detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3' UTR (2014t>c). The mutation I174V was also detected in 1 of 372 screened patients with temporal lobe epilepsy. We conclude that mutations in the EFHC1 gene may underlie different types of epilepsy syndromes.

EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality

“…Like variants associated with other diseases that have a complex genetic architecture, some EFHC1 variants may not be sufficient by themselves to cause epilepsy; however, they may have an additive effect toward the pathogenesis of JME disease in conjunction with other alleles associated with epilepsy. This would also explain the discovery of JME disease alleles in screened study controls 20,21 as well as in the case of multiple disease alleles in linkage disequilibrium and the autosomal dominant transmission with incomplete penetrance that we see in our large families.…”

“…14), were not available in 2004 when variants of the EF-hand domain (C-terminal) containing 1 gene (EFHC1) were reported as disease-causing mutations in myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions produced by juvenile myoclonic epilepsy (JME). Consequently, all EFHC1 variants discovered in the first decade of this millennium and reported with respect to epilepsy or not [15][16][17][18][19][20][21][22][23][24][25][26][27][28] have not been "vetted" through NHGRI and ACMG guidelines. More importantly, both NHGRI and ACMG guidelines advise that "with evidence on variants evolving" and the "content of sequencing tests expanding, " "rigorous evaluation" and "reanalysis of variants are encouraged" to prevent misannotation of the pathogenicity of variants in public databases.…”

Association Between Idiopathic Generalized Epilepsy and EFHC1 Gene Mutations of 662 G>A and 685 T>C

“…Ancak bu mutasyonun hasta ve kontrol grubunda eşit frekansta gö-rülmesi sebebiyle 685T>C mutasyonunun İJE ile ilişkili olmayabileceği görüşünü ileri sürmüşler-dir. 26 Çalışmamızda; Stogmann ve ark.nın bulgularını destekler şekilde, 685T>C mutasyonu, hasta ve kontrol grubu arasında istatistiksel olarak anlamlı bir fark oluşturmamıştır.…”

“…22 Sonraki yıllarda Alman toplumunda, İtalyan toplumunda, Avusturyalı İJE olgularında ve Avrupa kökenli JME'li hastalarda gerçekleştirilen çalışmalar, EFHC1 genindeki patojenik olabilecek mutasyonlar hakkında farklı sonuçlar ortaya çıkarmıştır. [23][24][25][26][27] Bu çalışmalarda, EFHC1 geni ile İJE sendromları arasındaki ilişkinin, toplumdan topluma farklı-lık gösterdiği ve özellikle genin 4. ekzonunda rastlanan 685 T>C ve 662G>A mutasyonlarının patojenik etkilerinin kimi toplumlarda gözlenirken, kimilerinde gözlenmediği saptanmıştır. Bu nedenler dikkate alınarak gendeki bu iki mutasyonun, Türk toplumunda hastalıkla ilişkisi bakımından araştırılması amaçlanmıştır.…”

Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5–6.0 Hz polyspike waves

“…These five Mendelian JME genes listed above account, in the least, for rare and scarce families with private mutations, with the exception of EFHC1, which accounts for at most 3–20% of JME cohorts (Stogmann et al. 2006; Annesi et al. 2007; Medina et al.…”